2. Academic Validation
  3. Dihydromyricetin attenuates intervertebral disc degeneration by inhibiting NLRP3 inflammasome activation via the Keap1/Nrf2/HO-1 pathway

Dihydromyricetin attenuates intervertebral disc degeneration by inhibiting NLRP3 inflammasome activation via the Keap1/Nrf2/HO-1 pathway

  • Eur J Pharmacol. 2025 Mar 8:998:177501. doi: 10.1016/j.ejphar.2025.177501.
Hainan Hong 1,  Di Guo 1,  Tao Xia 2,  Yuhang Zhang 3
Affiliations

Affiliations

  • 1 Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, China.
  • 2 Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, China. Electronic address: xiat6648@enzemed.com.
  • 3 Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, China; Enze Hospital, Taizhou Enze Medical Center (Group), Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, China. Electronic address: zhangyh3515@enzemed.com.
PMID: 40058758 DOI: 10.1016/j.ejphar.2025.177501
Abstract

Intervertebral disc degeneration (IVDD) is a highly prevalent chronic degenerative condition that significantly compromises patients' quality of life. Currently employed clinical treatments include surgical intervention and symptom management strategies; however, effective pharmacological strategies are lacking. Dihydromyricetin (DHM) has remarkable anti-inflammatory and antioxidative properties. On the basis of these biological characteristics, we hypothesized that DHM might have therapeutic potential in IVDD through its anti-inflammatory effects. Network pharmacology analysis revealed 130 overlapping targets between DHM and IVDD, with the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway emerging as a crucial regulatory axis. Experimental validation demonstrated that DHM treatment significantly ameliorated LSI-induced disc degeneration, as evidenced by reduced histopathological scores, upregulated expression of extracellular matrix (ECM) proteins. In vitro studies revealed that DHM effectively inhibited IL-1β-induced NOD-like Receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and Pyroptosis by decreasing Keap1 expression and activating the Nrf2/HO-1 signaling pathway. Specific silencing of Nrf2 significantly attenuated the protective effects of DHM, further confirming the crucial role of the Keap1/Nrf2/HO-1 pathway in the therapeutic action of DHM. Through integrated network pharmacology analysis and experimental validation, this study demonstrated for the first time that DHM alleviates IVDD by inhibiting Keap1-mediated Nrf2 degradation and activating the Nrf2/HO-1 pathway to suppress NLRP3 inflammasome-mediated Pyroptosis. Furthermore, these findings validate the therapeutic potential of natural bioactive compounds in IVDD, providing experimental evidence and a theoretical foundation for the development of novel therapeutic strategies against IVDD.

Keywords

Dihydromyricetin; Inflammation; Intervertebral disc degeneration; Nucleus pulposus; Pyroptosis.

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